Sulfonyltetrahydro-3H-benzo(E)indole-8-amine compounds as 5-hydroxytryptamine-6 ligands

ABSTRACT

The present invention provides a compound of formula I and the use thereof in the therapeutic treatment of a CNS disorder related to or affected by the 5-HT6 receptor

BACKGROUND OF THE INVENTION

This application claims the benefit under 35 U.S.C. §119(e) toco-pending U.S. provisional application No. 60/519,063, filed Nov. 10,2003, which is hereby incorporated by reference in its entirety.

Serotonin (5-Hydroxytryptamine)(5-HT) receptors play a critical role inmany physiological and behavioral functions in humans and animals. Thesefunctions are mediated through various 5-HT receptors distributedthroughout the body. There are now approximately fifteen different human5-HT receptor subtypes that have been cloned, many with well-definedroles in humans. One of the most recently identified 5-HT receptorsubtypes is the 5-HT6 receptor, first cloned from rat tissue in 1993(Monsma, F. J.; Shen, Y.; Ward, R. P.; Hamblin, M. W. MolecularPharmacology 1993, 43, 320-327) and subsequently from human tissue(Kohen, R.; Metcalf, M. A.; Khan, N.; Druck, T.; Huebner, K.; Sibley, D.R. Journal of Neurochemistry 1996, 66, 47-56). The receptor is aG-protein coupled receptor (GPCR) positively coupled to adenylatecyclase (Ruat, M.; Traiffort, E.; Arrang, J-M.; Tardivel-Lacombe, L.;Diaz, L.; Leurs, R.; Schwartz, J-C. Biochemical Biophysical ResearchCommunications 1993, 193, 268-276). The receptor is found almostexclusively in the central nervous system (CNS) areas both in rat and inhuman. In situ hybridization studies of the 5-HT6 receptor in rat brainusing mRNA indicate principal localization in the areas of 5-HTprojection including striatum, nucleus accumbens, olfactory tubercle,and hippocampal formation (Ward, R. P.; Hamblin, M. W.; Lachowicz, J.E.; Hoffman, B. J.; Sibley, D. R.; Dorsa, D. M. Neuroscience 1995, 64,1105-1111).

There are many potential therapeutic uses for 5-HT6 ligands in humansbased on direct effects and on indications from available scientificstudies. These studies include the localization of the receptor, theaffinity of ligands with known in vivo activity, and various animalstudies conducted so far.

One potential therapeutic use of modulators of 5-HT6 receptor functionis in the enhancement of cognition and memory in human diseases such asAlzheimer's. The high levels of receptor found in important structuresin the forebrain, including the caudate/putamen, hippocampus, nucleusaccumbens, and cortex suggest a role for the receptor in memory andcognition since these areas are known to play a vital role in memory(Gerard, C.; Martres, M.-P.; Lefevre, K.; Miquel, M. C.; Verge, D.;Lanfumey, R.; Doucet, E.; Hamon, M.; El Mestikawy, S. Brain Research,1997, 746, 207-219). The ability of known 5-HT6 receptor ligands toenhance cholinergic transmission also supported the potential cognitionuse (Bentley, J. C.; Boursson, A.; Boess, F. G.; Kone, F. C.; Marsden,C. A.; Petit, N.; Sleight, A. J. British Journal of Pharmacology, 1999,126(7), 1537-1542). Studies have found that a known 5-HT6 selectiveantagonist significantly increased glutamate and aspartate levels in thefrontal cortex without elevating levels of noradrenaline, dopamine, or5-HT. This selective elevation of neurochemicals known to be involved inmemory and cognition strongly suggests a role for 5-HT6 ligands incognition (Dawson, L. A.; Nguyen, H. Q.; Li, P. British Journal ofPharmacology, 2000, 130(1), 23-26). Animal studies of memory andlearning with a known selective 5-HT6 antagonist found some positiveeffects (Rogers, D. C.; Hatcher, P. D.; Hagan, J. J. Society ofNeuroscience, Abstracts 2000, 26, 680).

A related potential therapeutic use for 5-HT6 ligands is the treatmentof attention deficit disorders (ADD, also known as Attention DeficitHyperactivity Disorder or ADHD) in both children and adults. Because5-HT6 antagonists appear to enhance the activity of the nigrostriataldopamine pathway and because ADHD has been linked to abnormalities inthe caudate (Ernst, M; Zametkin, A. J.; Matochik, J. H.; Jons, P. A.;Cohen, R. M. Journal of Neuroscience 1998, 18(15), 5901-5907), 5-HT6antagonists may attenuate attention deficit disorders.

Early studies examining the affinity of various CNS ligands with knowntherapeutic utility or a strong structural resemblance to known drugssuggests a role for 5-HT6 ligands in the treatment of schizophrenia anddepression. For example, clozapine (an effective clinical antipsychotic)has high affinity for the 5-HT6 receptor subtype. Also, several clinicalantidepressants have high affinity for the receptor as well and act asantagonists at this site (Branchek, T. A.; Blackburn, T. P. AnnualReviews in Pharmacology and Toxicology 2000, 40, 319-334).

Further, recent in vivo studies in rats indicate 5-HT6 modulators may beuseful in the treatment of movement disorders including epilepsy (Stean,T.; Routledge, C.; Upton, N. British Journal of Pharmacology 1999, 127Proc. Supplement 131P and Routledge, C.; Bromidge, S. M.; Moss, S. F.;Price, G. W.; Hirst, W.; Newman, H.; Riley, G.; Gager, T.; Stean, T.;Upton, N.; Clarke, S. E.; Brown, A. M. British Journal of Pharmacology2000, 130(7), 1606-1612).

Taken together, the above studies strongly suggest that compounds whichare 5-HT6 receptor modulators, i.e. ligands, may be useful fortherapeutic indications including: the treatment of diseases associatedwith a deficit in memory, cognition, and learning such as Alzheimer'sand attention deficit disorder; the treatment of personality disorderssuch as schizophrenia; the treatment of behavioral disorders, e.g.,anxiety, depression and obsessive compulsive disorders; the treatment ofmotion or motor disorders such as Parkinson's disease and epilepsy; thetreatment of diseases associated with neurodegeneration such as strokeor head trauma; or withdrawal from drug addiction including addiction tonicotine, alcohol, and other substances of abuse.

Therefore, it is an object of this invention to provide compounds whichare useful as therapeutic agents in the treatment of a variety ofcentral nervous system disorders related to or affected by the 5-HT6receptor.

It is another object of this invention to provide therapeutic methodsand pharmaceutical compositions useful for the treatment of centralnervous system disorders related to or affected by the 5-HT6 receptor.

It is a feature of this invention that the compounds provided may alsobe used to further study and elucidate the 5-HT6 receptor.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I

wherein

-   -   X is CR₆R₇, O or S;    -   n is an integer of 1 or 2;    -   R₁ is H, halogen, CN, CHO, OR₉ or a C₁-C₆alkyl, aryl or        heteroaryl group each optionally substituted;    -   R₂ is an optionally substituted C₁-C₆alkyl, C₃-C₇cycloalkyl,        aryl or heteroaryl group or an optionally substituted 8- to        13-membered bicyclic or tricyclic ring system having a N atom at        the bridgehead and optionally containing 1, 2 or 3 additional        heteroatoms selected from N, O or S with the proviso that when X        is CH₂ then R₂ must be other than 4-methylphenyl;    -   R₃ is H, halogen, CN, OR₁₉, OCO₂R₁₀, CO₂R₁₁, CONR₁₂R₁₃,        SO_(x)R₁₄, NR₁₅R₁₆, COR₁₇, or a C₁-C₆alkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, C₃-C₇cycloalkyl, aryl or heteroaryl group each        optionally substituted;    -   R₄ and R₅ are each independently H or a C₁-C₆alkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl,        aryl or heteroaryl group each optionally substituted, or R₄ and        R₅ may be taken together with the atom to which they are        attached to form an optionally substituted 5- to 7-membered ring        optionally containing an additional heteroatom selected from O,        N or S;    -   R₆ and R₇ are each independently H or an optionally substituted        C₁-C₆alkyl group;    -   R₉, R₁₀, R₁₁, R₁₄, R₁₇, R₁₈ and R₁₉ are each independently H or        a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,        cycloheteroalkyl, aryl or heteroaryl group each optionally        substituted;    -   R₁₂ and R₁₃ are each independently H or an optionally        substituted C₁-C₆alkyl group or R₁₂ and R₁₃ may be taken        together with the atom to which they are attached to form a 5-        to 7-membered ring optionally containing another heteroatom        selected from O, NR₁₈ or SO_(m);    -   R₁₅ and R₁₆ are each independently H or an optionally        substituted C₁-C₄alkyl group or R₁₅ and R₁₆ may be taken        together with the atom to which they are attached to form a 5-        to 7-membered ring optionally containing another heteroatom        selected from O, NR₁₈ or SO_(m); and    -   x and m are each independently 0 or an integer of 1 or 2; or        a stereoisomer thereof or a pharmaceutically acceptable salt        thereof.

The present invention also provides methods and compositions useful inthe treatment of central nervous system disorders.

DETAILED DESCRIPTION OF THE INVENTION

The 5-hydroxytryptamine-6 (5-HT6) receptor is one of the most recentreceptors to be identified by molecular cloning. Its ability to bind awide range of therapeutic compounds used in psychiatry, coupled with itsintriguing distribution in the brain has stimulated significant interestin new compounds which are capable of interacting with or affecting saidreceptor. Significant efforts are being made to understand the role ofthe 5-HT6 receptor in psychiatry, cognitive dysfunction, motor functionand control, memory, mood and the like. To that end, compounds whichdemonstrate a binding affinity for the 5-HT6 receptor are earnestlysought both as an aid in the study of the 5-HT6 receptor and aspotential therapeutic agents in the treatment of central nervous systemdisorders, for example see C. Reavill and D. C. Rogers, Current Opinionin Investigational Drugs, 2001, 2(1):104-109, Pharma Press Ltd.

Surprisingly, it has now been found thatsulfonyltetrahydrobenzoindoleamine compounds of formula I demonstrate5-HT6 affinity along with significant sub-type selectivity.Advantageously, said formula I compounds are effective therapeuticagents for the treatment of central nervous system (CNS) disordersassociated with or affected by the 5-HT6 receptor. Accordingly, thepresent invention provides sulfonyldihydroimidazopyridinone compounds offormula I

wherein

-   -   X is CR₆R₇, O or S;    -   n is an integer of 1 or 2;    -   R₁ is H, halogen, CN, CHO, OR₉ or a C₁-C₆alkyl, aryl or        heteroaryl group each optionally substituted;    -   R₂ is an optionally substituted C₁-C₆alkyl, C₃-C₇cycloalkyl,        aryl or heteroaryl group or an optionally substituted 8- to        13-membered bicyclic or tricyclic ring system having a N atom at        the bridgehead and optionally containing 1, 2 or 3 additional        heteroatoms selected from N, O or S with the proviso that when X        is CH₂ then R₂ must be other than 4-methylphenyl;    -   R₃ is H, halogen, CN, OR₁₉, OCO₂R₁₀, CO₂R₁₁, CONR₁₂R₁₃,        SO_(x)R₁₄, NR₁₅R₁₆, COR₁₇, or a C₁-C₆alkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, C₃-C₇cycloalkyl, aryl or heteroaryl group each        optionally substituted;    -   R₄ and R₅ are each independently H or a C₁-C₆alkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl,        aryl or heteroaryl group each optionally substituted, or R₄ and        R₅ may be taken together with the atom to which they are        attached to form an optionally substituted 5- to 7-membered ring        optionally containing an additional heteroatom selected from O,        N or S;    -   R₆ and R₇ are each independently H or an optionally substituted        C₁-C₆alkyl group;    -   R₉, R₁₀, R₁₁, R₁₄, R₁₇, R₈ and R₁₉ are each independently H or a        C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,        cycloheteroalkyl, aryl or heteroaryl group each optionally        substituted;    -   R₁₂ and R₁₃ are each independently H or an optionally        substituted C₁-C₆alkyl group or R₁₂ and R₁₃ may be taken        together with the atom to which they are attached to form a 5-        to 7-membered ring optionally containing another heteroatom        selected from O, NR₁₈ or SO_(m);    -   R₁₅ and R₁₆ are each independently H or an optionally        substituted C₁-C₄alkyl group or R₁₅ and R₁₆ may be taken        together with the atom to which they are attached to form a 5-        to 7-membered ring optionally containing another heteroatom        selected from O, NR₁₈ or SO_(m); and    -   x and m are each independently 0 or an integer of 1 or 2; or        a stereoisomer thereof or a pharmaceutically acceptable salt        thereof.

As used in the specification and claims, the term halogen designates F,Cl, Br or I and the term cycloheteroalkyl designates a five- toseven-membered cycloalkyl ring system containing 1 or 2 heteroatoms,which may be the same or different, selected from N, O or S andoptionally containing one double bond. Exemplary of the cycloheteroalkylring systems included in the term as designated herein are the followingrings wherein X′ is NR, O or S; and R is H or an optional substituent asdescribed hereinbelow:

Similarly, as used in the specification and claims, the term heteroaryldesignates a five- to ten-membered aromatic ring system containing 1, 2or 3 heteroatoms, which may be the same or different, selected from N, Oor S. Such heteroaryl ring systems include pyrrolyl, azolyl, oxazolyl,thiazolyl, imidazolyl, furyl, thienyl, quinolinyl, isoquinolinyl,indolyl, benzothienyl, benzofuranyl, benzisoxazolyl or the like. Theterm aryl designates a carbocyclic aromatic ring system such as phenyl,naphthyl, anthracenyl or the like. The term haloalkyl as used hereindesignates a C_(n)H_(2n+1) group having from one to 2n+1 halogen atomswhich may be the same or different and the term haloalkoxy as usedherein designates an OC_(n)H_(2n+1) group having from one to 2n+1halogen atoms which may be the same or different.

Exemplary of the 8- to 13-membered bicyclic or tricyclic ring systemshaving a N atom at the bridgehead and optionally containing 1, 2 or 3additional heteroatoms selected from N, O or S included in the term asdesignated herein are the following ring systems wherein W is NR, O orS; and R is H or an optional substituent as described hereinbelow:

In the specification and claims, when the terms C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl, cycloheteroalkyl, aryl orheteroaryl are designated as being optionally substituted, thesubstituent groups which are optionally present may be one or more ofthose customarily employed in the development of pharmaceuticalcompounds, or the modification of such compounds, to influence theirstructure/activity, persistence, absorption, stability or otherbeneficial property. Specific examples of such substituents includehalogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl,haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl,alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsuphinyl,alkylsulphonyl, carbamoyl, alkylaminocarbonyl, phenyl, phenoxy, benzyl,benzyloxy, heteroaryl, indolyl, heterocyclyl or cycloalkyl groups,preferably halogen atoms or lower alkyl or lower alkoxy groups.Typically, 0-3 substituents may be present. When any of the foregoingsubstituents represents or contains an alkyl substituent group, this maybe linear or branched and may contain up to 12, preferably up to 6, morepreferably up to 4 carbon atoms.

Pharmaceutically acceptable salts may be any acid addition salt formedby a compound of formula I and a pharmaceutically acceptable acid suchas phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic,malonic, mandelic, succinic, fumaric, acetic, lactic, nitric, sulfonic,p-toluene sulfonic, methane sulfonic acid or the like.

Compounds of the invention include esters, carbamates or otherconventional prodrug forms, which in general, are functional derivativesof the compounds of the invention and which are readily converted to theinventive active moiety in vivo. Correspondingly, the method of theinvention embraces the treatment of the various conditions describedhereinabove with a compound of formula I or with a compound which is notspecifically disclosed but which, upon administration, converts to acompound of formula I in vivo. Also included are metabolites of thecompounds of the present invention defined as active species producedupon introduction of these compounds into a biological system.

Compounds of the invention may exist as one or more stereoisomers. Thevarious stereoisomers include enantiomers, diastereomers, atropisomersand geometric isomers. One skilled in the art will appreciate that onestereoisomer may be more active or may exhibit beneficial effects whenenriched relative to the other stereoisomer(s) or when separated fromthe other stereoisomer(s). Additionally, the skilled artisan knows howto separate, enrich or selectively prepare said stereoisomers.Accordingly, the present invention comprises compounds of formula I, thestereoisomers thereof and the pharmaceutically acceptable salts thereof.The compounds of the invention may be present as a mixture ofstereoisomers, individual stereoisomers, or as an optically active orenantiomerically pure form.

Preferred compounds of the invention are those compounds of formula Iwherein X is CR₆R₇. Another group of preferred compounds of theinvention are those formula I compounds wherein n is 1. Also preferredare those compounds of formula I wherein R₂ is an optionally substitutedaryl or heteroaryl group or an optionally substituted 8- to 13-memberedbicyclic or tricyclic ring system having a N atom at the bridgehead andoptionally containing 2 or 3 additional heteroatoms selected from N, Oor S.

More preferred compounds of the invention are those compounds of formulaI wherein X is CR₆R₇ and R₆ and R₇ are H. Another group of morepreferred compounds are those compounds of formula I wherein X is CH₂and R₂ is an optionally substituted phenyl or imidazothiazolyl group.

Among the preferred compounds of the invention are:

-   N,N-dimethyl-3-(phenylsulfonyl)-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;-   N,N-dimethyl-3-(2-naphthylsulfonyl)-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;-   3-[(4-fluorophenyl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;-   3-[(3,4-difluorophenyl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;-   3-[(2-chlorophenyl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;-   3-[(3-chlorophenyl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;-   3-[(2,3-dichlorophenyl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;-   3-[(2,4-diflorophenyl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;-   3-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;-   3-[(2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;-   N-methyl-3-(phenylsulfonyl)-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;-   N-methyl-3-[(2-chlorophenyl)sulfonyl]-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;-   3-(phenylsulfonyl)-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;-   N,N-dimethyl-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]quinolin-2-amine;-   N,N-dimethyl-7-(phenylsulfonyl)-2,3,4,7-tetrahydropyrano[2,3-e]indol-2-amine;-   N,N-dimethyl-7-(phenylsulfonyl)-2,3,4,7-tetrahydrothiopyrano[2,3-e]indol-2-amine;-   N,N-dimethyl-7-[(2-chlorophenyl]sulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]-quinolin-2-amine;-   N,N-dimethyl-7-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]quinolin-2-amine;-   N,N-dimethyl-7-[(2-chlorophenyl)sulfonyl]-2,3,4,7-tetrahydropyrano[2,3-e]indol-2-amine;-   N,N-dimethyl-7-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-2,3,4,7-tetrahydropyrano[2,3-e]indol-2-amine;-   N,N-dimethyl-7-[(2-chlorophenyl)sulfonyl]-2,3,4,7-tetrahydrothiopyrano[2,3-e]indol-2-amine;-   N,N-dimethyl-7-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-2,3,4,7-tetrahydrothiopyrano[2,3-e]indol-2-amine;-   a stereoisomer thereof; or-   a pharmaceutically acceptable salt thereof.

Advantageously, the present invention provides a process for thepreparation of a compound of formula I which comprises reacting acompound of formula II with a sulfonyl chloride, ClSO₂—R₂, in thepresence of a base, optionally in the presence of a solvent. The processis shown in flow diagram I.

Bases suitable for use in the process of the invention include strongbases such as NaH, KOt-Bu, diisopropylethylamine, or any conventionalbase capable of removing a proton from a nitrogen atom.

Solvents suitable for use in the process of the invention include polarsolvents such as tetrahydrofuran, dimethyl formamide, dimethylsulfoxide,lower alkyl alcohol, acetonitrile, or the like.

Compounds of formula II may be prepared using conventional syntheticmethods and, if required, standard isolation or separation procedures.For example, compounds of formula II wherein X is CH₂; R₁ and R₃ are H;and n is 1 (IIa) may be prepared according to the method described by C.Lin et al. in J. Heterocyclic Chemistry (1994), 31, 129-139; i.e., byreacting a protected tetrahydroindol-4-one of formula III with triethylphosphonoacetate and NaH to give the compound of formula IV; reducingthe formula IV compound with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone(DDQ) in dioxane to give the ester of formula V; hydrolyzing said esterwith NaOH in methanol/water to give the corresponding acid of formulaVI; reacting said acid with thionyl chloride to give the correspondingacid chloride and reacting said acid chloride with ethylene and AlCl₃ togive the formula VII ketone; reacting said ketone with an amine offormula VIII under reductive amination conditions (NaCNBH₃/aceticacid/tetrahydrofuran-methanol) to give the protected compound of formulaIX; and deprotecting said formula IX compound in the presence of an acidto give the desired compound of formula IIa. The reaction is shown inflow diagram II wherein P represents a protecting group.

Protecting groups suitable for use in the reactions shown hereinaboveinclude p-toluenesulfonyl, t-butoxycarbonyl, benzyl, acetyl,benzyloxycarbonyl, or any conventional group known to protect a basicnitrogen in standard synthetic procedures.

Compounds of formula II wherein X is O or S; R₁ and R₃ are H; and n is 1(IIb) may be prepared according to the method described in U.S. Pat. No.5,288,748; i.e., reducing a 3-nitropyrano or -thiopyrano compound offormula X to give the corresponding 3-amino compound of formula XI,alkylating said 3-amino compound using standard sequential alkylation orreductive alkylation techniques to give the compound of formula XII;nitrating the formula XII compound with fuming nitric acid and H₂SO₄ togive the 6-nitro compound of formula XIII; reducing the 6-nitro compoundwith zinc dust in acetic acid to give the 6-amino compound of formulaXIV; reacting said formula XIV compound with chloral hydrate andhydroxylamine HCl to give the compound of formula XV; cyclizing theformula XV compound with H₂SO₄ to give the diketone compound of formulaXVI; and reducing said diketone with LiAlH₄ to give the desired compoundof formula IIb. The reaction is shown in flow diagram III wherein X is Oor S and Hal represents Cl or Br.

Compounds of formula II wherein R₄ or R₅ are H may be converted tocompounds of formula I by first adding a protecting group, thensulfonylating as shown in flow diagram I to give the protected compoundof formula Ia and deprotecting to give the desired compound of formulaI. The reaction sequence is shown in flow diagram IV wherein Prepresents a protecting group. It is understood that either or both ofR₄ and R₅ may be H.

Protecting groups suitable for use in the reactions shown hereinaboveinclude p-toluenesulfonyl, t-butoxycarbonyl, benzyl, acetyl,benzyloxycarbonyl, or any conventional group known to protect a basicnitrogen in standard synthetic procedures.

Advantageously, the formula I compounds of the invention are useful forthe treatment of CNS disorders relating to or affected by the 5-HT6receptor including mood, personality, behavioral, psychiatric,cognitive, neurodegenerative, or the like disorders, for exampleAlzheimer's disease, Parkinson's disease, attention deficit disorder,anxiety, epilepsy, depression, obsessive compulsive disorder, sleepdisorders, neurodegenerative disorders (such as head trauma or stroke),feeding disorders (such as anorexia or bulimia), schizophrenia, memoryloss, disorders associated with withdrawal from drug or nicotine abuse,or the like or certain gastrointestinal disorders such as irritablebowel syndrome. Accordingly, the present invention provides a method forthe treatment of a disorder of the central nervous system related to oraffected by the 5-HT6 receptor in a patient in need thereof whichcomprises providing said patient a therapeutically effective amount of acompound of formula I as described hereinabove. The compounds may beprovided by oral or parenteral administration or in any common mannerknown to be an effective administration of a therapeutic agent to apatient in need thereof.

The term “providing” as used herein with respect to providing a compoundor substance embraced by the invention, designates either directlyadministering such a compound or substance, or administering a prodrug,derivative or analog which forms an equivalent amount of the compound orsubstance within the body.

The therapeutically effective amount provided in the treatment of aspecific CNS disorder may vary according to the specific condition(s)being treated, the size, age and response pattern of the patient, theseverity of the disorder, the judgment of the attending physician or thelike. In general, effective amounts for daily oral administration may beabout 0.01 to 1,000 mg/kg, preferably about 0.5 to 500 mg/kg andeffective amounts for parenteral administration may be about 0.1 to 100mg/kg, preferably about 0.5 to 50 mg/kg.

In actual practice, the compounds of the invention are provided byadministering the compound or a precursor thereof in a solid or liquidform, either neat or in combination with one or more conventionalpharmaceutical carriers or excipients. Accordingly, the presentinvention provides a pharmaceutical composition which comprises apharmaceutically acceptable carrier and an effective amount of acompound of formula I as described hereinabove.

Solid carriers suitable for use in the composition of the inventioninclude one or more substances which may also act as flavoring agents,lubricants, solubilizers, suspending agents, fillers, glidants,compression aides, binders, tablet-disintegrating agents orencapsulating materials. In powders, the carrier may be a finely dividedsolid which is in admixture with a finely divided compound of formula I.In tablets, the formula I compound may be mixed with a carrier havingthe necessary compression properties in suitable proportions andcompacted in the shape and size desired. Said powders and tablets maycontain up to 99% by weight of the formula I compound. Solid carrierssuitable for use in the composition of the invention include calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Any pharmaceutically acceptable liquid carrier suitable for preparingsolutions, suspensions, emulsions, syrups and elixirs may be employed inthe composition of the invention. Compounds of formula I may bedissolved or suspended in a pharmaceutically acceptable liquid carriersuch as water, an organic solvent, or a pharmaceutically acceptable oilor fat, or a mixture thereof. Said liquid composition may contain othersuitable pharmaceutical additives such as solubilizers, emulsifiers,buffers, preservatives, sweeteners, flavoring agents, suspending agents,thickening agents, coloring agents, viscosity regulators, stabilizers,osmo-regulators, or the like. Examples of liquid carriers suitable fororal and parenteral administration include water (particularlycontaining additives as above, e.g., cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g., glycols) or their derivatives,or oils (e.g., fractionated coconut oil and arachis oil). For parenteraladministration the carrier may also be an oily ester such as ethyloleate or isopropyl myristate.

Compositions of the invention which are sterile solutions or suspensionsare suitable for intramuscular, intraperitoneal or subcutaneousinjection. Sterile solutions may also be administered intravenously.Inventive compositions suitable for oral administration may be in eitherliquid or solid composition form.

For a more clear understanding, and in order to illustrate the inventionmore clearly, specific examples thereof are set forth hereinbelow. Thefollowing examples are merely illustrative and are not to be understoodas limiting the scope and underlying principles of the invention in anyway.

Unless otherwise stated, all parts are parts by weight. The terms HPLCand NMR designate high performance liquid chromatography and nuclearmagnetic resonance, respectively. The terms DMSO and THF designatedimethylsulfoxide and tetrahydrofuran, respectively; and the term EtOAcdesignates ethyl acetate.

EXAMPLE 1 Preparation of Ethyl{1-[(4-Methylphenyl)sulfonyl]-1,5,6,7-tetrahydro-4H-indol-4-ylidene}acetate

A mixture of1-[(4-methylphenyl)sulfonyl]-1,5,6,7-tetrahydro-1H-indol-4-one (7.33 g,25.3 mmol) in toluene under nitrogen is treated with NaH (60% in mineraloil, 1.31 g, 32.8 mmol), stirred for 5 min., treated dropwise withtriethylphosphonoacetate (9.08 g, 40.5 mmol) over a 10 min. period,heated at reflux temperature for 18 h, cooled to room temperature andpartitioned between ethyl acetate and water. The phases are separatedand the aqueous phase is further extracted with ethyl acetate. Theorganic phases are combined, washed with water, dried over MgSO₄ andconcentrated in vacuo. The resultant residue is chromatographed (silicagel, 25% ethyl acetate in hexane as eluent) to afford the title compoundas a colorless oil, 6.41 g (70% yield), identified by NMR and massspectral analyses.

EXAMPLE 2 Preparation of Ethyl1-{[(4-Methylphenyl)sulfonyl]-1H-indol-4-yl}acetate

A solution of ethyl{1-[(4-methylphenyl)sulfonyl]-1,5,6,7-tetrahydro-4H-indol-4-ylidene}acetate(359 mg, 1.0 mmol in dioxane under nitrogen is treated with a solutionof dichlorodicyanoquinone (DDQ) (341 mg, 1.5 mmol) in dioxane, heated atreflux temperature with stirring for 31 h, cooled to room temperatureand concentrated in vacuo. The resultant residue is chromatographed(silical gel, 25% ethyl acetate in hexanes as eluent) to afford thetitle compound as a red-brown gum, 175 mg (49% yield). identified by NMRand mass spectral analyses.

EXAMPLE 3 Preparation of1-{[(4-Methylphenyl)sulfonyl]-1H-indol-4-yl}acetic Acid

A solution of ethyl 1-{[(4-methylphenyl)sulfonyl]-1H-indol-4-yl}acetate(16.99 g, 47.5 mmol) in methanol is treated with 5N NaOH (36.7 mL),stirred under nitrogen for 4 h, concentrated in vacuo to remove themethanol, acidified with 6N HCl and extracted with ethyl acetate. Theextracts are combined, washed with water, dried over MgSO₄ andconcentrated in vacuo. The resultant residue is chromatographed (silicalgel, 50% ethyl acetate in hexanes as eluent) to afford the titlecompound as a light brown glass, 14.13 g (90% yield), identified by massspectral analyses.

EXAMPLE 4 Preparation of3-[(4-Methylphenyl)sulfonyl]-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-one

A solution of 1-{[(4-methylphenyl)sulfonyl]-1H-indol-4-yl}acetic acid(498 mg, 1.51 mmol) in CH₂Cl₂ it treated with thionyl chloride (0.225mL, 3.09 mmol) under nitrogen, stirred for 2 h and concentrated todryness in vacuo. The resultant residue is dissolved in CH₂Cl₂ andreevaporated. The process is repeated to remove the excess thionylchloride. The final oil residue is dissolved in CH₂Cl₂ and addeddropwise over a 15 minute period at −20° C. to a stirred mixture ofAlCl₃ in CH₂Cl₂ which has been presaturated with ethylene gas. Thereaction mixture is stirred and bubbled with ethylene gas at −20° C. for1 h, poured onto ice and extracted with CH₂Cl₂. The extracts arecombined, washed with water, dried over MgSO₄ and concentrated in vacuo.This residue is chromatographed (silica gel, CH₂Cl₂ as eluent) to affordthe title compound as beige crystals, 215 mg (42% yield), identified byNMR and mass spectral analyses.

EXAMPLE 5 Preparation ofN,N-Dimethyl-3{[(4-methylphenyl)sulfonyl]-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-yl}amine

A solution of3-[(4-methylphenyl)sulfonyl]-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-one(0.10 g, 0.73 mmol) 0.295 mmol) in THF is treated sequentially with 2Mdimethyl amine in THF (3 mL), sodium triacetoxyborohydride (0.28 g) and,acetic acid, stirred at room temperature for 5 days, quenched with waterand extracted with ether The aqueous phase is basified with 1N NaOH andextracted with ether. These extracts are combined, dried over MgSO₄ andconcentrated in vacuo to afford the title product as a semi-solid, 35mg, (14% yield), identified by NMR and mass spectral analyses.

EXAMPLE 6 Preparation ofN-(Cyclopropylmethyl)-3-[(4-methylphenyl)sulfonyl-]6,7,8,9-tetrahydro-3H-benzofelindol-8-amine

A solution of3-[(4-methylphenyl)sulfonyl]-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-one(2.0 g) in CH₂Cl₂ is treated sequentially with aminomethylcyclopropane((0.630 g, 1.5 eq.) and sodium triacetoxyborohydride (1.6 g, 1.3 eq.),stirred at room temperature for 16 h, quenched with 1N NaOH andextracted with CH₂Cl₂. The extracts are combined, dried over MgSO₄ andconcentrated in vacuo to give the title product, 2.2 g, identified byNMR and mass spectral analyses.

EXAMPLE 7 Preparation ofN,N-Dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine

A solution ofN,N-dimethyl-3{[(4-methylphenyl)sulfonyl]-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-yl}amine(0.035 g) in a 1:1 mixture of methanol:THF is treated with 0.5 mL ofNaOCH₃ (25% in methanol), heated at reflux temperature for 2 h, cooledand concentrated in vacuo. The resultant residue is diluted with waterand extracted with EtOAc. The extracts are combined, dried over MgSO₄and concentrated in vacuo to afford the title product, 0.015 g,identified by NMR and mass spectral analyses.

EXAMPLE 8 Preparation ofN,N-Dimethyl-3-(phenylsulfonyl)-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine

A solution of N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine(32 mg, 0.2 mmol) in THF is treated with benzenesulfonyl chloride (29.1mg, 0.22 mmol) followed by KOtBu (19.8 mg, 0.22 mmol), stirred at roomtemperature for 18 h and concentrated in vacuo. The resultant residue isdissolved in a mixture of DMSO, methanol and water and purified byGilson preparative HPLC¹ to give the title compound, [M+H] 369,retention time (RT) 2.067 minutes. ¹Gilson Preparative HPLC conditions:Gilson Preparative HPLC system; YMC Pro C18, 20 mm×50 mm ID, 5 uMcolumn; 2 mL injection; Solvent A: 0.02% TFA/water; Solvent B:0.02%TFA/acetonitrile; Gradient: Time 0: 95% A; 2 min: 95% A; 14 min: 10% A,15 min: 10% A, 16 min: 95% A; Flow rate 22.5 mL/min; Detection: 254 nmDAD.

EXAMPLES 9-27 Preparation ofN,N-Dimethyl-3-(arylisulfonyl)-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amineCompounds

Using essentially the same procedures described in Examples 5-8hereinabove and employing the appropriate amine and sulfonyl chloridereagents, the compounds shown on Table I are obtained and identified byHPLC² and mass spectral analyses.

TABLE I

Ex. RT No. R2 R4 R5 [M+H] (min)  9 4-trifluoromethoxyphenyl CH₃ CH₃ 4393.02 10 2-naphthyl CH₃ CH₃ 406 3.11 11 4-fluorophenyl CH₃ CH₃ 373 3.0012 2-chloro-4-(trifluoromethyl)phenyl CH₃ CH₃ 457 3.10 133,4-difluorophenyl CH₃ CH₃ 391 2.84 14 2-chlorophenyl CH₃ CH₃ 389 2.8615 3-chlorophenyl CH₃ CH₃ 389 2.93 16 2,3-dichlorophenyl CH₃ CH₃ 4242.93 17 2,4-difluorophenyl CH₃ CH₃ 391 2.89 186-chloroimidazo[2,1-b][1,3]thiazol-5-yl CH₃ CH₃ 435 2.87 192,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl CH₃ CH₃ 470 2.88 203,5-dimethylisoxazol-4-yl CH₃ CH₃ 374 2.73 21 4-methylphenyl Hcyclopropyl 381 1.965 22 4-methylphenyl H isopropyl 384 2.116 234-methylphenyl H C₄H₉ 398 2.216 24 4-methylphenyl H cyclobutyl 395 1.9925 4-methylphenyl H C₃H₇ 383 26 4-methylphenyl H CH₃ 355 1.99 274-methylphenyl C₃H₇ C₃H₇ 425 2.366

EXAMPLE 28 Comparative Evaluation of 5-HT6 Binding Affinity of TestCompounds

The affinity of test compounds for the serotonin 5-HT6 receptor isevaluated in the following manner. Cultured Hela cells expressing humancloned 5-HT6 receptors are harvested and centrifuged at low speed(1,000×g) for 10.0 min to remove the culture media. The harvested cellsare suspended in half volume of fresh physiological phosphate bufferedsaline solution and recentrifuged at the same speed. This operation isrepeated. The collected cells are then homogenized in ten volumes of 50mM Tris.HCl (pH 7.4) and 0.5 mM EDTA. The homogenate is centrifuged at40,000×g for 30.0 min and the precipitate is collected. The obtainedpellet is resuspended in 10 volumes of Tris.HCl buffer and recentrifugedat the same speed. The final pellet is suspended in a small volume ofTris.HCl buffer and the tissue protein content is determined in aliquotsof 10-25 μl volumes. Bovine Serum Albumin is used as the standard in theprotein determination according to the method described in Lowry et al.,J. Biol. Chem., 193:265 (1951). The volume of the suspended cellmembranes is adjusted to give a tissue protein concentration of 1.0mg/ml of suspension. The prepared membrane suspension (10 timesconcentrated) is aliquoted in 1.0 ml volumes and stored at −70° C. untilused in subsequent binding experiments.

Binding experiments are performed in a 96 well microtiter plate format,in a total volume of 200 μl. To each well is added the followingmixture: 80.0 μl of incubation buffer made in 50 mM Tris.HCl buffer (pH7.4) containing 10.0 mM MgCl₂ and 0.5 mM EDTA and 20 μl of [³H]-LSD(S.A., 86.0 Ci/mmol, available from Amersham Life Science), 3.0 nM. Thedissociation constant, K_(D) of the [³H]LSD at the human serotonin 5-HT6receptor is 2.9 nM, as determined by saturation binding with increasingconcentrations of [³H]LSD. The reaction is initiated by the finaladdition of 100.0 μl of tissue suspension. Nonspecific binding ismeasured in the presence of 10.0 μM methiothepin. The test compounds areadded in 20.0 μl volume.

The reaction is allowed to proceed in the dark for 120 min at roomtemperature, at which time, the bound ligand-receptor complex isfiltered off on a 96 well unifilter with a Packard Filtermate® 196Harvester. The bound complex caught on the filter disk is allowed to airdry and the radioactivity is measured in a Packard TopCount® equippedwith six photomultiplier detectors, after the addition of 40.0 μlMicroscint®-20 scintillant to each shallow well. The unifilter plate isheat-sealed and counted in a PackardTopcount® with a tritium efficiencyof 31.0%.

Specific binding to the 5-HT6 receptor is defined as the totalradioactivity bound less the amount bound in the presence of 10.0 μMunlabeled methiothepin. Binding in the presence of varyingconcentrations of test compound is expressed as a percentage of specificbinding in the absence of test compound. The results are plotted as log% bound versus log concentration of test compound. Nonlinear regressionanalysis of data points with a computer assisted program Prism® yieldedboth the IC₅₀ and the K_(i) values of test compounds with 95% confidencelimits. A linear regression line of data points is plotted, from whichthe IC₅₀ value is determined and the K_(i) value is determined basedupon the following equation:K _(i) =IC ₅₀/(1+L/K _(D))where L is the concentration of the radioactive ligand used and K_(D) isthe dissociation constant of the ligand for the receptor, both expressedin nM.

Using this assay, the following Ki values are determined and compared tothose values obtained by representative compounds known to demonstratebinding to the 5-HT6 receptor. The data are shown in Table II, below.

TABLE II Test Compound 5-HT6 binding Ki (Ex. No.) (nM)  8 1  9 79 10 1311 19 12 55 13 9 14 2 15 2 16 6 17 8 18 6 19 5 20 59 21 103 22 26 23 17324 36 25 12 27 173 Comparative Examples 5-HT6 binding Ki Clozapine 6.0Loxapine 41.4 Bromocriptine 23.0 Methiothepin 8.3 Mianserin 44.2Olanzepine 19.5

As can be seen from the data shown on Table II, the compounds of theinvention demonstrate significant affinity for the 5-HT6 receptor site.

1. A compound of formula I

wherein X is CR₆R₇, O or S; n is an integer of 1 or 2; R₁ is H, halogen,CN, CHO, OR₉ or a C₁-C₆alkyl, aryl or heteroaryl group each optionallysubstituted; R₂ is an optionally substituted C₁-C₆alkyl,C₃-C₇cycloalkyl, aryl or heteroaryl group or an optionally substituted8- to 13-membered bicyclic or tricyclic ring system having a N atom atthe bridgehead and optionally containing 1, 2 or 3 additionalheteroatoms selected from N, O or S with the proviso that when X is CH₂then R₂ must be other than 4-methylphenyl; R₃ is H, halogen, CN, OR₁₉,OCO₂R₁₀, CO₂R₁₁, CONR₁₂R₁₃, SO_(x)R₁₄, NR₁₅R₁₆, COR₁₇, or a C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl, aryl or heteroaryl groupeach optionally substituted; R₄ and R₅ are each independently H or aC₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, aryl or heteroaryl group each optionally substituted,or R₄ and R₅ may be taken together with the atom to which they areattached to form an optionally substituted 5- to 7-membered ringoptionally containing an additional heteroatom selected from O, N or S;R₆ and R₇ are each independently H or an optionally substitutedC₁-C₆alkyl group; R₉, R₁₀, R₁₁, R₁₄, R₁₇, R₁₈ and R₁₉ are eachindependently H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group eachoptionally substituted; R₁₂ and R₁₃ are each independently H or anoptionally substituted C₁-C₆alkyl group or R₁₂ and R₁₃ may be takentogether with the atom to which they are attached to form a 5- to7-membered ring optionally containing another heteroatom selected fromO, NR₁₈ or SO_(m); R₁₅ and R₁₆ are each independently H or an optionallysubstituted C₁-C₄alkyl group or R₁₅ and R₁₆ may be taken together withthe atom to which they are attached to form a 5- to 7-membered ringoptionally containing another heteroatom selected from O, NR₁₈ orSO_(m); and x and m are each independently 0 or an integer of 1 or 2; ora stereoisomer thereof or a pharmaceutically acceptable salt thereof. 2.The compound according to claim 1 wherein X is CR₆R₇.
 3. The compoundaccording to claim 1 wherein n is
 1. 4. The compound according to claim1 wherein R₂ is an optionally substituted aryl or heteroaryl group or anoptionally substituted 8- to 13-membered bicyclic or tricyclic ringsystem having a N atom at the bridgehead and optionally containing 2 or3 additional heteroatoms selected from N, O or S.
 5. The compoundaccording to claim 2 wherein n is 1 and R₆ and R₇ are H.
 6. The compoundaccording to claim 2 wherein R₄ and R₅ are each independently H orC₁-C₃alkyl.
 7. The compound according to claim 5 wherein R₂ is anoptionally substituted phenyl or imidazothiazolyl group.
 8. The compoundaccording to claim 7 wherein R₁ and R₂ are H and R₄ and R₅ are eachindependently H or CH₃.
 9. The compound according to claim 1 selectedfrom the group consisting of:N,N-dimethyl-3-(phenylsulfonyl)-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;N,N-dimethyl-3-(2-naphthylsulfonyl)-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;3-[(4-fluorophenyl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;3-[(3,4-difluorophenyl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;3-[(2-chlorophenyl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;3-[(3-chlorophenyl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;3-[(2,3-dichlorophenyl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;3-[(2,4-diflorophenyl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;3-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;3-[(2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;N-methyl-3-(phenylsulfonyl)-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;N-methyl-3-[(2-chlorophenyl)sulfonyl]-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;3-(phenylsulfonyl)-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;N,N-dimethyl-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]quinolin-2-amine;N,N-dimethyl-7-(phenylsulfonyl)-2,3,4,7-tetrahydropyrano[2,3-e]indol-2-amine;N,N-dimethyl-7-(phenylsulfonyl)-2,3,4,7-tetrahydrothiopyrano[2,3-e]indol-2-amine;N,N-dimethyl-7-[(2-chlorophenyl]sulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]-quinolin-2-amine;N,N-dimethyl-7-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]quinolin-2-amine;N,N-dimethyl-7-[(2-chlorophenyl)sulfonyl]-2,3,4,7-tetrahydropyrano[2,3-e]indol-2-amine;N,N-dimethyl-7-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-2,3,4,7-tetrahydropyrano[2,3-e]indol-2-amine;N,N-dimethyl-7-[(2-chlorophenyl)sulfonyl]-2,3,4,7-tetrahydrothiopyrano[2,3-e]indol-2-amine;N,N-dimethyl-7-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-2,3,4,7-tetrahydrothiopyrano[2,3-e]indol-2-amine;a stereoisomer thereof; and a pharmaceutically acceptable salt thereof.10. A pharmaceutical composition which comprises a pharmaceuticallyacceptable carrier and an effective amount of a compound of formula I

wherein X is CR₆R₇, O or S; n is an integer of 1 or 2; R₁ is H, halogen,CN, CHO, OR₉ or a C₁-C₆alkyl, aryl or heteroaryl group each optionallysubstituted; R₂ is an optionally substituted C₁-C₆alkyl,C₃-C₇cycloalkyl, aryl or heteroaryl group or an optionally substituted8- to 13-membered bicyclic or tricyclic ring system having a N atom atthe bridgehead and optionally containing 1, 2 or 3 additionalheteroatoms selected from N, O or S; R₃ is H, halogen, CN, OR₁₉,OCO₂R₁₀, CO₂R₁₃, CONR₁₂R₁₃, SO_(x)R₁₄, NR₁₅R₁₆, COR₁₇, or a C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl, aryl or heteroaryl groupeach optionally substituted; R₄ and R₅ are each independently H or aC₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, aryl or heteroaryl group each optionally substituted,or R₄ and R₅ may be taken together with the atom to which they areattached to form an optionally substituted 5- to 7-membered ringoptionally containing an additional heteroatom selected from O, N or S;R₆ and R₇ are each independently H or an optionally substitutedC₁-C₆alkyl group; R₉, R₁₀, R₁₁, R₁₄, R₁₇, R₁₈ and R₁₉ are eachindependently H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group eachoptionally substituted; R₁₂ and R₁₃ are each independently H or anoptionally substituted C₁-C₆alkyl group or R₁₂ and R₁₃ may be takentogether with the atom to which they are attached to form a 5- to7-membered ring optionally containing another heteroatom selected fromO, NR₁₈ or SO_(m); R₁₅ and R₁₆ are each independently H or an optionallysubstituted C₁-C₄alkyl group or R₁₅ and R₁₆ may be taken together withthe atom to which they are attached to form a 5- to 7-membered ringoptionally containing another heteroatom selected from O, NR₁₈ orSO_(m); and x and m are each independently 0 or an integer of 1 or 2; ora stereoisomer thereof or a pharmaceutically acceptable salt thereof.11. The composition according to claim 10 having a formula I compoundwherein X is CR₆R₇.
 12. The composition according to claim 11 having aformula I compound wherein n is
 1. 13. The composition according toclaim 12 having a formula I compound wherein R₂ is an optionallysubstituted phenyl or imidazothiazolyl group.
 14. The compositionaccording to claim 10 having a formula I compound selected from thegroup consisting of:N,N-dimethyl-3-(phenylsulfonyl)-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;N,N-dimethyl-3-(2-naphthylsulfonyl)-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;3-[(4-fluorophenyl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;3-[(3,4-difluorophenyl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;3-[(2-chlorophenyl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;3-[(3-chlorophenyl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;3-[(2,3-dichlorophenyl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;3-[(2,4-diflorophenyl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;3-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;3-[(2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-N,N-dimethyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;N-methyl-3-(phenylsulfonyl)-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;N-methyl-3-[(2-chlorophenyl)sulfonyl]-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;3-(phenylsulfonyl)-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine;N,N-dimethyl-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]quinolin-2-amine;N,N-dimethyl-7-(phenylsulfonyl)-2,3,4,7-tetrahydropyrano[2,3-e]indol-2-amine;N,N-dimethyl-7-(phenylsulfonyl)-2,3,4,7-tetrahydrothiopyrano[2,3-e]indol-2-amine;N,N-dimethyl-7-[(2-chlorophenyl]sulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]-quinolin-2-amine;N,N-dimethyl-7-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]quinolin-2-amine;N,N-dimethyl-7-[(2-chlorophenyl)sulfonyl]-2,3,4,7-tetrahydropyrano[2,3-e]indol-2-amine;N,N-dimethyl-7-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-2,3,4,7-tetrahydropyrano[2,3-e]indol-2-amine;N,N-dimethyl-7-[(2-chlorophenyl)sulfonyl]-2,3,4,7-tetrahydrothiopyrano[2,3-e]indol-2-amine;N,N-dimethyl-7-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-2,3,4,7-tetrahydrothiopyrano[2,3-e]indol-2-amine;a stereoisomer thereof; and a pharmaceutically acceptable salt thereof.